Hieken, T. J.

Abstract Background: While there are abundant data on the surgical management of BC after neoadjuvant chemotherapy (NAC), there is less guidance regarding surgical management of BC after NET, particularly with respect to lymph node (LN) surgery. While pathologic complete response (pCR) is common with NAC, it is a rare event with NET. In this analysis we assess the surgeons’ approach in the context of NET. Methods: The ALTERNATE trial is a phase III study that randomized postmenopausal patients (pts) with clinical stage II/III ER+ HER2- BC to receive neoadjuvant anastrozole (A), fulvestrant (F), or both for 6 mos. before surgery. The primary objective was to determine if neoadjuvant F or A+F increases the rate of pCR or ypT1-2N0/N1mic/Ki67 <2.7% residual disease over A alone. Breast surgery was per standard of care. Sentinel lymph node biopsy (SLNB) with or without axillary lymph node dissection (ALND) was required to determine preoperative endocrine prognostic index PEPI score and residual cancer burden (RCB). Surgeons were required to indicate if the patient would be eligible for breast- conserving surgery (BCS) prior to NET. Patient accrual occurred from 2014-2018. The surgical outcomes are reported for the entire group. Results: Among the 3 treatment arms, 933 patients completed 6 cycles of NET. The clinical T stage at diagnosis was 73.6% T2, 22.6% T3and 3.8% T4. Initial tumor size was assessed by mammogram and ultrasound. Primary tumor histology was ductal in 64.8% and lobular in 25.4%.568 pts (60.9%) were clinically node negative (cN0), 36.2% cN1, 2.6% cN2 with 0.3% cN3. LNs were palpable in 25.2%. 383 had LN needle biopsy pre NET, of which 80.9% were positive. The surgeons’ initial impression of the patient’s eligibility for BCS was 74% while 0.6% were considered inoperable.75.5% of pts had post-NET imaging performed. Of those with tumor size recorded, 52.9% were T1 or not visible. Overall, 69.9% of the 933 patients had BCS. Of those 330 pts without post-NET imaging or who had post-NET imaging without a size noted, 64.8% underwent BCS. For pts undergoing BCS, 80.2% required only one surgery for margin clearance. Of the 690 pts deemed eligible for BCS pre NET, 79% had BCS. Of the 240 pts deemed ineligible for BCS pre-NET, 43.8% had BCS. Of the pre-NET cT2 tumors, 79% had BCS while only 45.5% of T3 tumors and 37.1% of T4 tumors had BCS. On surgical pathology, 474 (50.8%) pts were LN+ compared to pre-NET cN+ 39.1% and needle biopsy-proven 33.2%. For pts with pN0, 93.3% had SLNB alone. 6.7 % of pN0 had ALND alone or SLNB+ALND. For those with pN1-3 , 36.3% had SLN only; 37.3% SLN+ ALND; 26.4% ALND alone. Only 0.8% of the patients had no ALND or SLNB performed. Pts undergoing BCS were more likely to have SLNB alone for a +SLN compared to mastectomy pts (62.9% vs. 37.6%; chi-square p<0.0001). For pts with pre-NET +LN on needle biopsy, only 26.8% underwent SLNB alone, while 37.4% underwent ALND alone. Of the 204 LN-positive pts having SLNB alone, 55.9% had only 1 + LN and 27% had only 2+ LNs. For pN+ pts who underwent SLNB +ALND, 42.1% had 1-2 + LNs. Conclusion: With NET, 69.9% of pts achieved BCS, including 43.8% deemed ineligible pre-NET. Given the low rate of pCR to NET, there should not be the expectation of pCR in +LNs. Based on the procedures performed in pts with +SLNs, it appears that surgeons were applying ACOSOG Z0011 criteria for pts having BCS, but were less likely to omit ALND for +LN in pts having mastectomy. The finding of only 1-2 +LNs in many of the LN+ pts suggests that omission of ALND may be a reasonable approach post-NET. Longer follow-up is required to assess local-regional recurrence. Support: U10CA180821, U10CA180882; https://acknowledgments.alliancefound.org. Clinical Trials.gov Identifier: NCT01953588 Citation Format: A. M. Leitch, T. Dockter, V. suman, A. Weiss, G. W. Unzeitig, J. Guenther, S. Sanati, K. Vij, J. Hoog, A. Caudle, A. Tiersten, M. Mita, W. Razaq, T. J. Hieken, Y. Wang, M. Rimawi, M. J. Ellis, E. Winer, K. K. Hunt, A. H. Partridge, L. A. Carey. Surgical outcomes in the ALTERNATE trial (Alliance A011106) -a randomized phase 3 neoadjuvant endocrine therapy (NET) trial in postmenopausal women with clinical stage II/III estrogen receptor positive (ER+) and HER2 negative (HER2-) breast cancer (BC) [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr RF1-02.

Abstract Introduction: Hormone receptor positive (HR+), HER2- breast cancer (BC) is the most common subtype of BC. Despite advances in chemotherapy and endocrine therapy optimization, local and systemic recurrences frequently occur, especially for patients with node-positive disease. Recent data suggest a subset of patients with this tumor phenotype may benefit from the addition of anti-Programmed Death-1(aPD1) to neoadjuvant chemotherapy. However, T-cell infiltration (TCI), a biomarker of response to aPD1 and chemotherapy, is typically low in this BC subtype. Preclinical models show that combining preoperative radiation therapy (preop RT) with immune checkpoint inhibitors can enhance TCI and anti-tumor immunity. We conducted the first randomized trial to test whether no-, low- or high-dose RT combined with aPD1 increases TCI and improves responses in non-irradiated, metastatic lymph nodes in HR+/HER2- BC (NCT04443348). Materials & Methods: Eligible patients had ER and/or PR≥10%, HER2 negative invasive BC with clipped and biopsy-proven positive axillary node(s), cT1c-T4c, cN1-3, and at least one of the following criteria: grade 3 or grade 1-2 with cN2-N3, Ki67 >20%, or high genomic assay score. Between 2022-2024, 51 patients from 10 centers were randomized to no (0Gy; control arm), low (9Gy) or high (24Gy) doses of preop RT to the primary tumor with concurrent pembrolizumab followed by a 2-week tumor biopsy. Stratification factors were T1c vs. T2-4 and N1 vs. N2-3. Patients subsequently received pembrolizumab with 12 weeks of paclitaxel, followed by 4 cycles of adriamycin-cyclophosphamide (q2wk or q3wk) with pembrolizumab (200 mg q3 wks or 400 mg q6 wks). Surgery and adjuvant therapy followed standard-of-care. Dual co-primary endpoints were 2wk tumor TCI and nodal pathologic complete response (ypN0) at time of definitive surgery. TCI was assessed by multiplex immunofluorescence (pan-cytokeratin, CD3, CD8), using a rank-based Immunoscore (range 0-1), compared to baseline reference biopsies via two-tailed Mann-Whitney test. ypN0 was evaluated non-comparatively. Secondary endpoints included pCR and Residual Cancer Burden (RCB) 0/1. Results: Among 51 patients enrolled, 49 were evaluable for TCI and 48 for the ypN0 endpoint. Median age was 49.5 years (range 23-78). The cohort had a high-risk clinical profile: 92% had cT2-4, 50% N2-3, and 62% grade 3 tumors. Median ER and PR positivity were 90% (20-100) and 68% (1-98), respectively. Multifocal or multicentric tumors were present in 32%. TCI was assessed at 2 weeks post-treatment. The proportion of tumors with TCI in the upper quartile increased with RT dose escalation: 31% (0Gy), 40% (9Gy), and 53% (24Gy). Median TCI scores at 2 weeks were 0.60 (0Gy), 0.56 (9Gy), and 0.82 (24Gy), compared to a median baseline value of 0.50 from untreated reference samples. A statistically significant increase in TCI was observed only in the 24Gy cohort relative to the untreated group (p=0.027). 70.8% underwent mastectomy, with 39.6% receiving immediate reconstruction. 8% experienced G2/3 wound complications, balanced across arms. Median number of lymph nodes removed was 6.5 (1-42). The overall ypN0 rate was 29%, and 24%(0Gy), 29%(9Gy) and 33%(24Gy) per arm. pCR/RCB 0-1 rates were 18%/27% in the entire cohort and 6%/18%(0Gy), 29%/29%(9Gy), and 19%/33%(24Gy), respectively. Conclusion: The addition of 24Gy preop RT to aPD1 significantly increased tumor TCI in HR+/HER2- early-stage BC. Non-irradiated nodal response rates were promising despite over one-third of the study population with grade 1/2 tumors and high disease burden, laying the foundation for a future randomized trial comparing the efficacy of this novel approach against standard of care for node-positive HR+/HER2- BC. Citation Format: G. Gupta, A. Y. Ho, F. Gharibpoor, Y. Abdou, J. D. Anampa, R. C. Blitzblau, B. C. Calhoun, D. L. Casey, S. F. Dent, L. A. Carey, J. R. Bellon, L. E. Warren, J. Lu, T. J. Hieken, A. G. Taghian, A. Bardia, T. Traina, G. Plitas, K. Gallagher, K. Daugherty, A. Thompson, I. Krop, A. Wolff, E. Mittendorf, J. Fox, H. Garber, E. Hwang, A. J. Khan, J. P. Loene, R. Mutter, S. Patil, C. Santa-Maria, B. V. Vincent, J. L. Wright, L. Spring.Primary Results from the HR+/HER2- Cohort of TBCRC-053 (P-RAD): A Randomized Trial of No, Low, or High Dose Preoperative RADiation with Pembrolizumab and Chemotherapy in Node-Positive, HER2-Negative Breast Cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr GS2-05.